Much attention has been paid to oxidising amyloid-β peptides (Aβ) for inhibiting their aggregation using photosensitive materials. However, the low penetration of ultraviolet/visible light into biological tissues and low targeting properties of the materials hinder their application. Here, we constructed a novel platform for attenuating the neurotoxicity of Aβ through functional upconversion nanoparticles (UCNPs@SiO2-ThS). UCNPs@SiO2-ThS can not only inhibit the aggregation of Aβ42 monomers, but also disassemble Aβ42 fibrils by its selective photooxidative capacity under the irradiation of near-infrared (NIR) light. Moreover, based on the enhancement of ThS fluorescence after attaching to Aβ42 fibrils, only Aβ42 fibrils exposed to both UCNPs@SiO2-ThS and light can be oxidized rather than other normal proteins. To further enhance Aβ-target photooxygenation, we introduced the Aβ-target peptide (KLVFF) on the surface. Compared to traditional chemotherapies and radiotherapies, this novel PDT strategy shows remarkably reduced side effects and improved targeting.
Qiang-Ming Li,Hui-Hui Han,Dan-Dan Zang,Xue-Qiang Zha,An Zhou,Feng-Yun Zhang,Jian-Ping Luo
An amyloid-β (Aβ) fibril is a vital pathogenic factor of Alzheimer’s disease (AD). Aβ fibril disintegrators possess great potential to be developed into novel anti-AD agents. Here, a ligand fishing method was employed to rapidly discover Aβ42 fibril disintegrators from Ganoderma lucidum using Aβ42 fibril-immobilized magnetic beads, which led to the isolation of six Aβ42 fibril disintegrators including ganodermanontriol, ganoderic acid DM, ganoderiol F, ganoderol B, ganodermenonol, and ergosterol. Neuroprotective evaluation in vitro exhibited that these Aβ42 fibril disintegrators could significantly mitigate Aβ42-induced neurotoxicity. Among these six disintegrators, ergosterol and ganoderic acid DM with stronger protecting activity were further selected to evaluate their neuroprotective effect on AD in vivo. Results showed that ergosterol and ganoderic acid DM could significantly alleviate Aβ42-induced cognitive dysfunction and hippocampus neuron loss in vivo. Moreover, ergosterol and ganoderic acid DM could significantly inhibit Aβ42-induced neuron apoptosis and Nrf2-mediated neuron oxidative stress in vitro and in vivo.
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